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Visualization of the function of the insulin receptor

Insulin was discovered almost 100 years ago. Now, a German-American research team with DZD involvement was able to show how the hormone activates its receptor. The results and images have been published in the' Journal of Cell Biology'.

Inactive IRs exhibit an inverted U-shaped ectodomain conformation. Upon insulin binding, the ectodomain of the receptor changing from a U-shaped to a T-shaped structure. Source: Gutmann et al.

 

Insulin is an important hormone for metabolism in the human body. It is mainly used to channel glucose from the blood into the cells. The hormone acts as a key that opens the cells for the glucose molecules. Insulin docks to the insulin receptors on the cell surface. The receptors then change their shape on the inside of the cell to transmit the signal. However, the exact nature of the structural change has not been known so far.

In order to gain an insight into receptor activation, the researchers have purified complete human insulin receptors and embedded them in nanodiscs. These are disk-shaped miniature membranes, which are just a few nanometers in size and could be made visible directly under the electron microscope. They were able to observe the insulin receptor in an artificial membrane and its structural changes.  

In the absence of insulin, the receptor exhibits an inverted U-shaped ectodomain conformation and well-separated transmembrane domains. Insulin binding results in structural rearrangements of the receptor. The receptor takes on a T-shaped structure that allows the transmembrane domains to come together. That's probably what triggers the signal transmission.

“These nanodisc-embedded receptors provide a novel platform to address further questions regarding insulin receptor regulation and eventually to test therapeutic agents”, said Dr. Ünal Coskun, co-senior author of the study and group leader at the DZD - Paul-Langerhans-Institute Dresden of the Helmholtz-Zentrum München at the University Hospital and the Medical Faculty Carl Gustav Carus of the TU Dresden.

Researchers from PLID and Rockefeller University collaborated on the study.

Original-Publication:
Gutmann, Kim et al. (2018): Visualization of ligand-induced transmembrane signaling in the full-length human insulin receptor. Journal of Cell Biology, DOI: 10.1083/jcb.201711047